Transition State Analogues Enhanced by Fragment-Based Structural Analysis: Bacterial Methylthioadenosine Nucleosidases

Di Zhang, Brandon E. Burdette, Zhengyu Wang, Kumari Karn, Hong Yu Li, Vern L. Schramm, Peter C. Tyler, Gary B. Evans, Shanzhi Wang

Research output: Contribution to journalArticle

Abstract

Transition state analogue inhibitor design (TSID) and fragment-based drug design (FBDD) are drug design approaches typically used independently. Methylthio-DADMe-Immucillin-A (MTDIA) is a tight-binding transition state analogue of bacterial 5′-methylthioadenosine nucleosidases (MTANs). Previously, Salmonella enterica MTAN structures were found to bind MTDIA and ethylene glycol fragments, but MTDIA modified to contain similar fragments did not enhance affinity. Seventy-five published MTAN structures were analyzed, and co-crystallization fragments were found that might enhance the binding of MTDIA to other bacterial MTANs through contacts external to MTDIA binding. The fragment-modified MTDIAs were tested with Helicobacter pylori MTAN and Staphylococcus aureus MTANs (HpMTAN and SaMTAN) as test cases to explore inhibitor optimization by potential contacts beyond the transition state contacts. Replacement of a methyl group with a 2′-ethoxyethanol group in MTDIA improved the dissociation constant 14-fold (0.09 nM vs 1.25 nM) for HpMTAN and 81-fold for SaMTAN (0.096 nM vs 7.8 nM). TSID combined with FBDD can be useful in enhancing already powerful inhibitors.

Original languageEnglish (US)
Pages (from-to)831-835
Number of pages5
JournalBiochemistry
Volume59
Issue number7
DOIs
StatePublished - Feb 25 2020

ASJC Scopus subject areas

  • Biochemistry

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    Zhang, D., Burdette, B. E., Wang, Z., Karn, K., Li, H. Y., Schramm, V. L., Tyler, P. C., Evans, G. B., & Wang, S. (2020). Transition State Analogues Enhanced by Fragment-Based Structural Analysis: Bacterial Methylthioadenosine Nucleosidases. Biochemistry, 59(7), 831-835. https://doi.org/10.1021/acs.biochem.9b01092